The invention relates to a process for the preparation of oral-application pharmaceutical compositions containing as the active substance aminoalkyl-1,1-diphosphonic acid derivatives, free acids, pharmaceutically compatible salts or hydrates thereof (hereinafter called by the general term bisphosphonates).
Bisphosphonates are important in the treatment of bone diseases and some disturbances of calcium metabolism such as hypercalcaemia, osteoporosis, tumour osteolysis, Paget""s disease, etc.
Pharmaceutical preparations in general have to satisfy exacting requirements regarding content, uniformity of content and purity. Special properties of active substances may adversely influence the content, uniformity and purity of the form of administration. It is known that bisphosphonates are a group of substances with a strong tendency to form complexes with polyvalent metal ions. Conventional pharmaceutical preparations for oral application are usually produced in installations and apparatus with metal surfaces, and consequently when bisphosphonates are processed the highly complex-forming active substance comes into contact with complexable material. This is particularly the case when water or aqueous media are used in processing. One remedy is dry processing, particularly on the direct tableting principle, since wet granulation is avoided in that case. Direct tableting is a very suitable method for producing high-dosage tablets. As is known, however, high-dosage forms of bisphosphonates for oral administration are particularly subject to compatibility problems, which makes oral treatment difficult. Aminodiphosphonic acids in particular cause irritation of the upper gastrointestinal tract (H. Fleisch, Bisphosphonates in Bone Disease, Herbert Fleisch, Berne, 1993; pages 126-131). In direct tableting furthermore, as in the case when non-granulated powder is filled into gelatine capsules, there is a risk of fluctuations in content, particularly for low or very low-dosage active substances. For this reason wet granulation is indispensable, in spite of the said risk of complex-forming. When high-speed mixers are used, the active substance is mixed with adjuvants and is granulated wet with water or aqueous binder solution. In the process the active substance is brought into very intensive contact with the metal surfaces of the apparatus. The risk of complex-forming can be additionally increased by the abrasive effect of some pharmaceutical adjuvants.
The object of the invention therefore is to develop a process for the preparation of bisphosphonate-containing pharmaceutical compositions for oral application, preferably containing up to 50 mg of active substance per unit dose, so as to reduce the loss of active substance in the preparation of the compositions.
To this end, according to the invention, bisphosphonates are converted by known fluidised-bed granulation (Liebermann et al. xe2x80x9cPharmaceutical Dosage Formsxe2x80x9d: Tablets, 2nd Ed. 1990, Marcel Dekker, New York, Basle; Pietsch: xe2x80x9cSize Enlargement by Agglomerationxe2x80x9d, John Wiley and Sons, Chichester) into formulations suitable for oral application. Fluidised-bed granulation is a conventional method of wet granulation. Unexpectedly, however, this method can reduce the loss of active substance or the diminution in content of active substance in the formulation to less than 6% by weight, preferably less than 4% by weight.
The invention thus relates to a process for the preparation of pharmaceutical compositions for the oral application of bisphosphonates, wherein the bisphosphonate is wet-granulated in manner known per se in a fluidised-bed granulator with adjuvants and wherein the wet granulate is then dried in the fluidised-bed granulator, screened through a screen having a suitable mesh width and further processed by techniques known per se to form pharmaceutical compositions for oral administration to a patient in unit dosage form.